Search

New chimeric inhibitors targeting the epidermal growth factor (EGFR) and histone deacetylases (HDACs) were synthesized and tested for antineoplastic efficiency in solid cancer (prostate and hepatocellular carcinoma) and leukemia/lymphoma cell models. The most promising compounds, 3BrQuin-SAHA and 3ClQuin-SAHA, showed strong inhibition of tumor cell growth at one-digit micromolar concentrations with IC50 values similar to or lower than those of clinically established reference compounds SAHA and gefitinib. Target-specific EGFR and HDAC inhibition was demonstrated in cell-free kinase assays and Western blot analyses, while unspecific cytotoxic effects could not be observed in LDH release measurements. Proapoptotic formation of reactive oxygen species and caspase-3 activity induction in PCa and HCC cell lines DU145 and Hep-G2 seem to be further aspects of the modes of action. Antiangiogenic potency was recognized after applying the chimeric inhibitors on strongly vascularized chorioallantoic membranes of fertilized chicken eggs (CAM assay). The novel combination of two drug pharmacophores against the EGFR and HDACs in one single molecule was shown to have pronounced antineoplastic effects on tumor growth in both solid and leukemia/lymphoma cell models. The promising results merit further investigations to further decipher the underlying modes of action of the novel chimeric inhibitors and their suitability for new clinical approaches in tumor treatment.

BackgroundWith the development of radiotherapy technology, radiotherapy has been increasingly used to treat primary hepatocellular carcinoma (HCC). However, due to radioresistance and the intolerance of the adjacent organs to radiation, the effects of radiotherapy are often unsatisfactory. Therefore, it is necessary to study radiosensitization in HCC.MethodA microarray was used to analyze the genes that were significantly associated with radiosensitivity. HCC cells, HepG2 and MHCC97H, were subjected to radiation in vitro. Real-time PCR was performed to determine MIR22HG (microRNA22 host gene) and miR-22-5p expression levels. Western blotting was performed to determine histone expression levels. A histone deacetylase (HDAC) whole cell assay was used to determine the activity of HDAC2. MTT, colony formation, 5-ethynyl-2′-deoxyuridine, and wound healing assays were performed to examine the function of MIR22HG and miR-22-5p in cellular radiosensitivity. Chromatin immunoprecipitation-PCR was used to confirm that HDAC2 affects the acetylation level of the MIR22HG promoter region. Finally, animal experiments were performed to demonstrate the in vivo effect of MIR22HG on the radiosensitivity of hepatoma.ResultsIrradiation can up-regulate MIR22HG expression and down-regulate HDAC2 expression. Inhibition of HDAC2 expression promotes histone acetylation in the MIR22HG promoter region and up-regulates MIR22HG expression. MIR22HG can increase radiosensitivity via miR-22-5p in HCC.ConclusionInhibition of HDAC2 expression promotes histone acetylation in the MIR22HG promoter region, thereby up-regulating the expression of MIR22HG and promoting the production of miR-22-5p, and ultimately increasing the sensitivity of liver cancer radiotherapy.

Background: With the development of radiotherapy technology, Radiotherapy has been used increasingly to treat primary hepatocellular carcinoma (HCC). But due to the radioresistance and the intolerance of the adjacent organs, the effect of radiotherapy is not satisfactory. Therefore, it is necessary to study the radiosensitization of HCC. Method: Microarray was used to analyze the significant gene associated with radiosensitivity. Application of HCC cells HepG2 and MHCC97H in vitro. Real-time PCR performed to determine MIR22HG (microRNA22 host gene) and miR-22-5p expression, western blot performed to determine histone expression. HDAC whole cell assay was sed to determine the activity of HDAC2. Then, MTT, colony formation, EDU, wound healing assays were to examine the function of MIR22HG and miR-22-5p on cellular radiosentivity. ChIP-PCR was used to confirm that HDAC2 affects the acetylation level of the MIR22HG promoter region. Finally, animal experiments were performed to demonstrate the effect MIR22HG on the radiosensitivity of hepatoma in vivo. Results: Irradiation can upregulate MIR22HG expression and downregulate HDAC2 expression; Inhibition of HDAC2 expression promotes histone acetylation in the MIR22HG promoter region and up-regulates MIR22HG expression; MIR22HG can increase radiosensitivity via miR-22-5p in HCC. Conclusion: Inhibition of HDAC2 expression promotes histone acetylation in the MIR22HG promoter region, thereby upregulating the expression of MIR22HG and promoting the production of miR-22-5p, ultimately increasing the sensitivity of liver cancer radiotherapy. Funding: This work was supported by the National Natural Science Foundation of China (81872473), Key R & D projects of Hunan science and technology planning project (2017SK2052). Declaration of Interest: The authors declare no conflicts of interest. Ethical Approval: All experiments were approved by the Animal Center of China South University and performed following International Guidelines and Protocols.